Background:The cell adhesion molecule P-selectin has an important role in the pathophysiology of thrombosis. The effect on venous thromboembolism (VTE) of increased circulating concentrations of soluble P-selectin (sP-selectin) and their association with the P-selectin variant Thr715Pro is still uncertain. Methods: This study was a case-control study of 116 patients with confirmed recurrent VTE and at least 1 event of unprovoked deep venous thrombosis or pulmonary embolism, and 129 age-and sex-matched healthy individuals. We measured sP-selectin by ELISA and P-selectin gene (SELP) variation by genotyping and sampled blood after a mean interval of 2.55 years after the most recent VTE event. Results: The mean (SD) sP-selectin concentration was higher in patients than in controls: 47.3 (15.0) g/L vs 36.8 (11.0) g/L, P <0.001. The unadjusted odds ratio (OR) for sP-selectin >55.1 g/L, representing the 95th percentile for controls, was 8.5 (95% CI, 3.7-23.3; P <0.001) and increased after adjustment for factor V Leiden, the prothrombin G20210A variant, increased factor VIII, and hyperhomocysteinemia (OR, 10.6; 95% CI, 4.1-31.2; P <0.001). Pro715 carriers were more prevalent among controls than patients (21.7% vs 14.7%).

Background and ObjectivesThe metabolic syndrome, defined by abdominal obesity, elevation of blood pressure, fasting glucose and triglycerides and low levels of high-density lipoprotein cholesterol is associated with atherosclerotic disease. It induces a pro-inflammatory and prothrombotic state. Despite its high prevalence, data on the association with venous thromboembolism (VTE) are scarce. The aim of our study was to elucidate the association of the metabolic syndrome with the risk of VTE. Design and MethodsWe conducted a case-control study to investigate the presence of the metabolic syndrome defined according to guidelines of the National Cholesterol Education Program, in high-risk patients with objectively confirmed recurrent VTE, who had had at least one unprovoked event of deep venous thrombosis or pulmonary embolism. Age and sex-matched healthy individuals served as controls. ResultsA total of 116 patients and 129 controls were enrolled. The prevalence of the metabolic syndrome was statistically significantly higher in patients (40/116, 35%) than in controls (26/129, 20%, p=0.012 Interpretation and ConclusionsThe metabolic syndrome may contribute to the development of VTE and is associated with a two-fold increased risk of VTE.

Summary. Background: Clotting factor (F) VIII is an independent risk factor for primary and recurrent venous thromboembolism (VTE). The causes for high plasma FVIII levels are not fully understood, but an involvement of genetic factors has been demonstrated. A multifunctional endocytic receptor, lowdensity lipoprotein receptor-related protein 1 (LRP1), mediates cellular uptake and subsequent degradation of FVIII and may contribute to variations in FVIII levels. Objective: We assessed the association of a genetic variation of LRP1 (663C > T) with basal FVIII levels and the risk of venous thrombosis in a group of high-risk patients and in healthy controls. Patients and methods: One hundred and fifty-two patients with a history of recurrent VTE (median age 56 years, 47% women) were compared with 198 age-and sex-matched controls (median age 53 years, 50% women). The LRP1 663C > T genotype was analyzed by mutagenic separated polymerase chain reaction assay and heterozygosity was confirmed by sequence analysis. Results: LRP1 663C > T genotype distribution differed significantly between patients (663CC n ¼ 138, 663CT n ¼ 14) and controls (663CC n ¼ 190, 663CT n ¼ 8; P ¼ 0.048). In multivariable linear regression analysis including LRP1 663C > T, ABO blood group, von Willebrand factor antigen, C-reactive protein and age, LRP1 663CT was independently associated with FVIII activity (P ¼ 0.02). LRP1 663CT was also associated with increased odds for VTE following adjustment for blood group O, FV Leiden and the prothrombin variation 20210G > A in multivariate analysis (odds ratio 3.3, 95% CI 1.3-8.5). Conclusions: According to our data the LRP1 663C > T polymorphism influences plasma FVIII levels independently of blood group, C-reactive protein and von Willebrand factor and is significantly associated with the risk of VTE.

There is accumulating evidence for an association between atherosclerosis and venous thrombosis, which may share common risk factors. The metabolic syndrome (MetSyn), a cluster of interrelated risk factors comprising abdominal obesity, elevated blood pressure, high triglycerides, reduced high-density lipoprotein cholesterol and elevated fasting glucose plasma levels is associated with atherosclerotic disease and type 2 diabetes mellitus. It induces a proinflammatory and prothrombotic state. Despite its high prevalence, data on the association with venous thromboembolism (VTE) are scarce. Therefore, we aimed to investigate the association of the MetSyn with the risk for VTE and conducted a case-control study to evaluate the prevalence of the MetSyn according to guidelines of the National Cholesterol Education Program in a high-risk population of patients with objectively confirmed recurrent VTE, who had at least one unprovoked event of deep venous thrombosis or pulmonary embolism. Age and sex-matched healthy individuals served as controls. Finally, a total of 116 patients (53 female, mean age +/−SD: 56 years +/−12) and 129 controls (66 female, mean age +/−SD: 53 years +/−11) were recruited between January 2005 and November 2005. The prevalence of the MetSyn was statistically significantly higher in patients (40/116, 35%) than in controls (26/129, 20%, p=0.012). The unadjusted odds ratio (OR) of the MetSyn for VTE was 2.1 (95% CI [1.2–3.7], p=0.012) and remained statistically significant after adjustment for factor V Leiden, prothrombin G20210A variation and elevated factor VIII activity, sex and age (OR=2.2, 95% CI [1.1–4.2], p=0.024). Furthermore, individuals with the MetSyn (n=66) had significantly higher hs-CRP (median, [interquartile range]: 0.312 mg/dL, [0.142–0.751] vs. 0.153 mg/dL, [0.073–0.330], p<0.001), fibrinogen (390 mg/dL, [342–432] vs. 343 mg/dL, [310–394], p<0.001) and factor VIII activity (182%, [157–216] vs. 159%, [133–199], p=0.005) compared to those without (n=179). In conclusion, the MetSyn was statistically significantly overrepresented in patients with VTE compared to control subjects without a history of venous or arterial thrombosis. Our data suggest that the MetSyn may contribute to the development of VTE as it was associated with a 2-fold increased risk for VTE.

Clotting factor VIII (FVIII) is an independent risk factor for primary and recurrent venous thromboembolism (VTE). Various causes for high plasma FVIII levels have been identified and an involvement of genetic factors has been demonstrated. Currently, the underlying genetic components have not been fully elucidated. A multifunctional endocytic receptor, low-density lipoprotein receptor-related protein 1 (LRP1), mediates cellular uptake and subsequent degradation of factor VIII, and seems to contribute to variations in FVIII levels. We assessed the effect of a genetic variation in the coding region of the LRP1 gene (LRP1 663C>T) on basal FVIII levels and the risk of venous thrombosis in a high risk group of patients and healthy controls. One-hundred-fifty-two patients with a history of recurrent VTE (median age = 56 years, 25th – 75th percentile: 44 – 63, 47% women) were compared with 198 age- and sex-matched healthy controls (median age = 53 years, 25th – 75th percentile: 44–59, 50% women) in a case-control study. All patients had at least one spontaneous VTE. The LRP1 663C>T genotype was analysed by mutagenic separated polymerase chain reaction assay. Heterozygosity was confirmed by sequence analysis in all cases. The LRP1 663CC genotype was found in 138 patients and 190 controls, LRP1 663CT in 14 patients and 8 controls, respectively. No homozygous individuals were identified. Genotype distributions did not significantly deviate from Hardy-Weinberg-equilibrium in patients (p=0.6) and controls (p=0.8). Heterozygous individuals were approximately twice as frequent among patients as controls (9% versus 4%, p=0.048). LRP1 663CT was associated with increased odds for VTE in multivariate analysis adjusted for blood group 0, factor V Leiden and the prothrombin variation 20210G>A (OR=3.3, 95% CI [1.3–8.5]). In all study participants (n=350) LRP1 663CT carriers (n=22) had significantly higher factor VIII activity (median=193%, 25th − 75th percentile: 158 – 222) than LRP1 663CC carriers (n=328, median=160%, 25th – 75th percentile: 125 – 195, p=0.01). Blood group 0 was significantly less frequent among patients (18 %) than controls (32 %, p = 0.002) and was associated with significantly lower factor VIII activity levels (n=91, median: 118%, 25th – 75th percentile: 95 – 155) compared to blood group non-0 (n=259, median: 175%, 25th – 75th percentile: 143 – 212, p < 0.001). Particularly high factor VIII activity levels were found in persons with a combination of LRP1 663CT and an AB0 blood group non-0 (n=16, median: 209%, 25th – 75th percentile: 192 – 231). In conclusion, we present evidence that the LRP1 663C>T polymorphism is associated with higher factor VIII plasma levels. Our study is the first report of a significantly increased thrombosis risk in heterozygous carriers of the LRP1 663C>T polymorphism. Prospective studies will have to prove, whether this parameter could serve as predictive marker for risk of venous thrombosis.